A number of 5-substituted phenoxyuracils are described in the chemistry literature. 5-Phenoxyuracil was first prepared by T. B. Johnson and H. H. Guest in Am. Chem. J., 42, 271 (1909). The same compound was prepared by B. R. Baker, J. L. Kelley in J. Med. Chem., 13, 461 (1970) and was tested as an inhibitor of FUDR phosphorylase and found to have poor activity. These same authors in a subsequent publication in J. Med. Chem., 14, 812 (1971) tested this same compound as an inhibitor of thymidine phosphorylase and found it to have poor activity.
A number of 5-substituted phenoxyuracils including unsubstituted phenoxy-, m-fluorophenoxy-, o-tolyloxy- and p-tolyloxyuracil were synthesized for cancer chemotherapeutic testing by Chun-Nien Chang, Shih-An Yang, Tien-Tu Wang and Yen Hu in Yao-Hsueh Pao 10, 600, 1963 (Acta Pharmaceutica Sinica 10, 600, and abstracted in CA 60: 14504b). In preliminary biological testing these authors found that m-fluorophenoxyuracil inhibited the growth of sarcoma 180 in mice.
A number of 5-substituted phenoxythiouracils are claimed in U.S. Pat. No. 2,697,708 and Brit. Pat. No. 706,253 as being active against Neurovaccinia infection. R. L. Thompson, M. Price, S. A. Minton, Jr., E. A. Falco and G. H. Hitchings in J. Immunol., 67, 483 (1951) describe the protection of mice against vaccinia virus by the administration of 5-substituted phenoxythiouracils. E. A. Falco, P. B. Russell and G. H. Hitchings in J. Am. Chem. Soc., 73, 4466 (1951) describe the preparation of some 5-substituted phenoxy 2-thiouracils including the preparation of 5-m-tolyloxy-2-thiouracil.
U.S. Pat. No. 3,154,551 describes the preparation of 2,4-dihydroxy-5-arylmercaptopyrimidines via the general method of condensing a thiophenol with 5-bromouracil. Brit. Pat. No. 951,431 describes similar compounds but neither of these patents discloses 5-(m-methylthiophenoxy)uracil or 5-(p-methylthiophenoxy)uracil. B. Roth and G. H. Hitchings in J. Org. Chem., 26, 2771 (1961) describe the inability of the authors to prepare 5-(p-methylphenoxy)uracil by reaction of 5-bromouracil with p-cresol.
Brit. Pat. No. 971,307 on the subject of 5-anilinopyrimidines describes the physical properties of 5-(m-methylanilino)uracil which was tested as an antibacterial and antimetabolic agent. Substantially the same subject matter is disclosed in U.S. Pat. No. 3,238,308. A subsequent publication by F. R. Geins, A. Perrotta and G. H. Hitchings in J. Med. Chem., 9, 108 (1966) discusses substantially similar subject matter.
M. R. Atkinson, G. Shaw and G. Sugowaz in J. Chem. Soc., 3207 (1957) describe the preparation of a number of 5-substituted phenylsulfonyl uracils as part of an antimetabolite study.
T. Zsolnai in Biochem. Pharmacol., 11, 995 (1962) describes the preparation of p-chloro- and p-methoxy-phenylhydrazinouracil for testing as fungistatic agents.
U.S. Pat. No. 3,922,345 on the subject matter of pyrimidinones having bronchodilator and antiulcer activities claims 5-(m-methylphenoxy)-2-(1H)pyrimidinone and the method of treating peptic ulcer which comprises administering to a subject afflicted therewith a daily dose of the above compound equivalent to about 0.60 to 21 mg. per kg. body weight. This patent also discloses the use of 4-hydroxy-5-(m-methylphenoxy)pyrimidine as a bronchodilator.
We have discovered that in rats, monkeys and human subjects 5-(m-methylphenoxy)-2-(1H)pyrimidinone is rapidly and efficiently metabolically converted to 5-m-tolyloxyuracil. The literature teaches that 5-substituted uracils such as 5-fluorouracil are metabolically converted to 5,6-dihydrouracils which undergo ring opening with subsequent loss of the C.sub.2 pyrimidine carbon as carbon dioxide. We have discovered that 5-m-tolyloxyuracil unexpectedly does not undergo this metabolic degradation in rats and monkeys. Finally, we have discovered that 5-m-tolyloxyuracil has a much longer plasma half life in human subjects than does 5-(m-methylphenoxy)-2-(1H)pyrimidinone.